Author ORCID Identifier

Date Available


Year of Publication


Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation





First Advisor

Ann M Stowe, PhD

Second Advisor

Daniel Lee, PhD


Type-2 diabetes (T2D) is a metabolic disorder that increases the risk for cerebrovascular disease and dementia and is associated with the progression of Alzheimer's Disease; however, the mechanisms responsible for T2D-associated dementia are still poorly understood. T2D leads to alterations of the innate and adaptive immune response that contribute to its progression, but how these cells contribute to cognitive decline during T2D is unknown. As there are no approved therapeutics for T2D that modulate the immune response, it is important that we investigate how peripheral immune cells contribute to cognitive decline during T2D. Amylin is an amyloidogenic hormone synthesized and co-secreted with insulin from pancreatic ß-cells that has been shown to contribute to the development and progression of T2D, cognitive decline, and AD pathology. Amylin deposits in the brain microvasculature and leads to cerebral amylin vasculopathy. We have shown that inducing amylin dyshomeostasis in rats by pancreatic-specific hypersecretion of human amylin (HIP rats) leads to cerebral amylin vasculopathy, neuroinflammation, and neurological deficits. Here, we tested the hypothesis that neuroinflammation caused by hypersecretion of pancreatic amylin leads to a dysregulated peripheral immune response that alters the immune profiles of the brain. We used HIP rats to determine the relationship between neuroinflammation and the impact of amylin on the peripheral immune response and immune cell migration into the brain. Using RNA sequencing, we found that hypersecretion of pancreatic amylin leads to altered genes in the brain involved in neuroinflammation and immune cell signaling, such as antigen presentation, B cell development, and T cell responses. Immune profiling showed a decrease in splenic immune cells that, in turn, led to a decrease in immune cell migration to the brains of HIP rats. As well as alterations in the blood. We then found that amylin led to alterations in proteins responsible for immune cell migration into the brain, such as ICAM-1 and VCAM-1. To determine how amylin acutely impacted the immune response, we injected wild-type (WT) rats with aggregated amylin. We found that amylin led to immune alterations in the spleen and blood but no changes in the brain. Next, we sought to determine a mechanism for the dysregulated immune response seen in HIP rats. To do this, we used mice that also hypersecrete pancreatic human amylin (HIP mice). In HIP mice, we were able to replicate our results seen in rats, showing a reduction in lymphocyte population in the spleen. Furthermore, we found that high levels of amylin are able to cause immune cell dysregulation by affecting hematopoiesis and B cell development, characterized by alteration of B cells and B cell progenitors in the spleen and bone marrow and an overall decrease of B cells in the brain, through the CXCL12/CXCR4 axis. These data show evidence for the role of pancreatic amylin and how it contributes to type-2 diabetic pathology by altering the peripheral and neuroimmune response. This gives rise to the potential for using immunotherapy to reverse and prevent the progression of type-2 diabetic cognitive decline.

Digital Object Identifier (DOI)

Available for download on Tuesday, October 01, 2024